Homeostatic regulation of blood neutrophil counts

Abstract

Blood neutrophil counts are determined by the differentiation and proliferation of precursor cells, the release of mature neutrophils from the bone marrow, margination, trafficking and transmigration through the endothelial lining, neutrophil apoptosis, and uptake by phagocytes. This brief review summarizes the regulation of blood neutrophil counts, which is in part controlled by G-CSF, IL-17, and IL-23. Neutrophils are retained in the bone marrow through interaction of CXCL12 with its receptor CXCR4. The relevance of this mechanism is illustrated by rare diseases in which disrupting the desensitization of CXCR4 results in failure to release mature neutrophils from bone marrow. Although blood neutrophil numbers in inbred mouse strains and individual human subjects are tightly controlled, their large variation among outbred populations suggests genetic factors. One example is benign ethnic neutropenia, which is found in some African Americans. Reduced and elevated neutrophil counts, even within the normal range, are associated with excess all-cause mortality.

Figure 1. Normal range of neutrophil counts in humans and mice

A) Neutrophil counts from 25,000 US Americans from (81) modified to show cumulative incidence. Mean counts in African Americans were significantly lower than in Caucasian or Hispanic individuals. B) Neutrophil counts in inbred mouse strains. Neutrophil counts calculated from white blood counts and relative neutrophils counts from 129S1/SvlMJ (n=29), BALB/cJ (n=16), FVB/NJ (n=24) and C57BL6/6J (n=19) from the Jackson laboratory phenome database (84, 85).

Figure 2. Relationship between excess mortality and white blood count

Nearly 4000 individuals from the Baltimore/Washington area were observed from to 1958–2002. Excess mortality as difference between observed and expected mortality hazard over time is plotted against white blood cell count. The dashed lines represent the 95% confidence intervals (with permission from (82).